Male circumcision has been shown to be clinically effective in reducing HIV acquisition rates in African men. The scientific rationale for the reduction in HIV transmission remains unknown, and work in our laboratory has shown that the mechanism is much more complex than those theorized early on (regarding keratin thicknesses and number of potential HIV target cells). We have found that more dynamic properties of the penile epithelia, such as permeability and inflammatory responses, may play more important roles. This proposal endeavors to further explore changes in penile epithelia after male circumcision, which relate to the skin's barrier function, and to compare them to previously circumcised and uncircumcised cohorts. Adjunct studies will focus on studies of baseline junctional protein expression in the foreskin and clinical factors that may affect HIV susceptibiliy in men. With these studies, we hope to gain a better understanding of how HIV is sexually transmitted in the male genital tract, how male circumcision works to prevent this, and how to develop effective future strategies in HIV prevention. PUBLIC HEALTH RELEVANCE: It is clear that male circumcision decreases the rate of female-to-male HIV acquisition. The studies proposed here seek to define the mechanism of protection. Understanding this mechanism should lead to new strategies which can decrease female-to-male HIV sexual transmission.